EP0651735A1 - Pharmacologically active alpha-(tertiary-aminomethyl)-phenylmethanol derivatives - Google Patents

Pharmacologically active alpha-(tertiary-aminomethyl)-phenylmethanol derivatives

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Publication number
EP0651735A1
EP0651735A1 EP93916373A EP93916373A EP0651735A1 EP 0651735 A1 EP0651735 A1 EP 0651735A1 EP 93916373 A EP93916373 A EP 93916373A EP 93916373 A EP93916373 A EP 93916373A EP 0651735 A1 EP0651735 A1 EP 0651735A1
Authority
EP
European Patent Office
Prior art keywords
benzenemethanol
methyl
dimethylamino
methylethoxy
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP93916373A
Other languages
German (de)
French (fr)
Other versions
EP0651735B1 (en
Inventor
Nils-Erik Willman
Bengt Christer Hans SJÖGREN
Lennart Gustav Nordh
Gustav Lennart Persson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Health AB
Original Assignee
Pharmacia and Upjohn AB
Pharmacia AB
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Publication of EP0651735A1 publication Critical patent/EP0651735A1/en
Application granted granted Critical
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
    • C07C217/70—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring

Definitions

  • the present invention relates to novel ⁇ -(tertiary- aminomethyl) -benzenemethanol derivatives having pharmacological properties, and to processes for their preparation.
  • the invention also relates to pharmaceutical compositions containing these derivatives and methods of treatment therewith.
  • Urinary incontinence is a very common disorder in both men and women. Large or smaller amounts of urine are involuntarily expelled from the bladder. There are two main types of urinary incontinence, i.e. urge incontinence and stress incontinence. Very few drugs are available for treatment of the latter type and they have been found to have low efficacy and significant side-effects.
  • PRIOR ART DD-A-210 031 discloses a process for the preparation of pharmacologically active l-aryl-2-aminoethanols. Specifically described are phenylethanolamines which are either unsubstituted or mono-substituted in phenyl ring positions 2 or 4 , or tri-substituted in positions 3, 4 and 5.
  • EP-A-103 830 discloses growth-promoting phenylethanolamine derivatives. No compounds di-substituted in positions 2 and 3 of the phenyl ring are specifically described.
  • EP-A-213 108 discloses pharmaceutical formulations containing an ⁇ - and/or ⁇ -sympathicomimetic agent in the form of a phenylethanolamine derivative. The only specific compound mentioned is 1- (3 ' -hydroxyphenyl) -2-aminoethanol .
  • US-A-4 , 349, 549 discloses hypertensively active ⁇ -aryl- ⁇ - hydroxyalkyl-spiropiperidine heterocycles.
  • R is selected from alkyl, alkoxy, alkenyloxy, arylalkox alkylthio and alkenylthio;
  • R 2 is selected from halogen, hydroxy, alkyl, alkoxy, alkenyloxy, alkylthio, alkenylthio, alkylamino, trifluoromethyl, cyano, nitro, alkylsulfinyl, alkylsulfonyl and acyl;
  • R 3 and R 4 either independently represent alkyl or alkenyl, or R 3 and R 4 are interconnected to form a heterocyclic system with the nitrogen atom, optionally containing one or more additional heteroatoms; and physiologically acceptable salts thereof.
  • the present invention provides the compounds having the general formula I above for therapeutica use, especially as urination controlling agents.
  • the present invention provides method of treating a living body suffering from a disorder related to urinary incontinence, which method comprises the step of administering to the said living body an effective amount of a compound having the general formula I above.
  • the present invention provides a pharmaceutical composition comprising one or more compounds o the general formula I above as the active ingredient, preferably together with a pharmaceutically acceptable carrie and, if desired, other pharmacologically active agents.
  • the present invention provides the us of the compounds having the general formula I above for the manufacture of a medicament for the treatment of urination control disorders.
  • the present invention provides processes for preparing compounds having the general formula above.
  • alkyl separately and in combinations such as alkylthio, alkylamino, alkylsulfinyl and alkylsulfonyl, i ⁇ meant to include straight and branched, saturated hydrocarbon groups.
  • alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, n-pentyl, n-hexyl.
  • alkenyl separately and in combinations such as alkenyloxy and alkenylthio, is meant to include straight and branched hydrocarbon groups containing one or more unsaturations.
  • alkenyl groups are ethenyl, propenyl, butenyl, pentenyl, hexenyl, methylpropenyl, ethylbutenyl.
  • alkoxy separately and in combinations such as arylalkoxy, is meant to include straight and branched, saturated alkoxy groups.
  • Exemplary alkoxy groups are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, n-pentyloxy, n-hexyloxy.
  • alkenyloxy is meant to include straight and branched alkenyloxy groups containing one or more unsaturations.
  • alkenyloxy groups are ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, methylpropenyloxy, ethylbutenyloxy.
  • aryl separately and in combinations, is meant to include aromatic systems that are either heterocyclic or only carbon-containing.
  • heterocyclic aromatic systems are thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, isobenzofuran, benzothiazole, benzothiophene, indole, isoindole, oxadiazole, benzoxazole.
  • Exemplary of only carbon-containing aromatic systems are phenyl and naphthyl .
  • acyl is meant to include straight, branched or cyclic, saturated, unsaturated or aromatic acyl groups.
  • acyl groups are formyl, acetyl, propionyl, butyryl, succinyl, crotonyl, cinna oyl, benzoyl.
  • halogen is meant to include fluoro, chloro, bromo and iodo.
  • R 1 is preferably selected from alkoxy and lower alkylthi having 1-5 carbon atoms.
  • R2 is preferably selected from halogen, alkoxy, alkylthio, trifluoromethyl, cyano, nitro, lower alkylsulfinyl, lower alkylsulfonyl and lower acyl; lower alkyl, lower acyl and lower alkoxy preferably containing 1-5 carbon atoms.
  • R 3 and R 4 are preferably, independently, selected from the group consisting of lower alkyl having 1-5 carbon atoms, or R 3 and R4 , together with the nitrogen atom, form a 5- or 6 membered heterocyclic ring such as pyrrolidine, piperidine, morpholine.
  • the general formula I includes the enantiomeric and racemic forms.
  • the compounds of formula I which contain salt- forming basic nitrogen atoms may also be in the form of salts suitable for pharmacological use.
  • R 1 and R 2 are as previously defined, is reductively alkylated with an aldehyde to form a compound of the general formula I.
  • Method a) above (which is illustrated further in Example 1 below) may be carried out by mixing the reagents, or the reagents may be dissolved or suspended in an inert solvent such as an alcohol, e.g. ethanol, water, dimethyl sulfoxide, acetonitrile etc. Mixtures of more than one solvent may be employed.
  • a suitable temperature range for the reaction is between about 20 °C and about 150 °C, usually between about 20 °C and about 100 °C.
  • the resulting product may be isolated by conventional procedures.
  • the starting material of formula II may be prepared from compounds of the general formula IV by methods described in Reference (1) in the list of References at the end of the description.
  • the crude epoxide II is preferably directly reacted with the desired amine.
  • the amino ketone III may be reduced by using a conventional reducing agent, such as LiAlH 4 BH3-THF, NaBH 4 etc., or by catalytic hydrogenation.
  • the process may be carried out in an inert solvent compatible with the reducing agent, e.g. hydrocarbons, ethers, alcohols, carboxylic acids. Mixtures of more than one solvent may also be employed.
  • a ⁇ uitable temperature range for carrying out the process is between about 20 °C and about 100 °C.
  • the starting material III may be prepared by using general methods as described in Reference (2) .
  • Method c) (which is illustrated further in Example 3 below) may be carried out in an excess of the non- activated amine NR 3 R 4 R 5 or in an inert solvent medium, usually at -70 °C or below.
  • the reactive derivative of the amine may, for example, be LiCH 2 NR 3 R , wherein R 3 and R 4 are lower alkyl groups or together form a ⁇ aturated ring system.
  • the reactive amine derivatives can be prepared according to the method described in Reference (3) or from (n-C 4 H g ) 3 SnCH 2 NR 3 R 4 described in Reference (4) .
  • the starting amines, such as CH 3 NR 3 R 4 ' are known compounds.
  • Compounds having the general formula IV are known co pound ⁇ or can be prepared by conventional method ⁇ a ⁇ described in Reference (5) .
  • the process may be carried out in an inert organic solvent compatible with the reducing agent, suitably at a temperature between about 20 °C and about 100 °C.
  • This reduction may also be performed by catalytic hydrogenation in per se known manner.
  • the starting material of the general formula V may be prepared from ⁇ -hydroxybenzeneacetic acid derivatives by per se known methods or be prepared from compounds of the general formula IV by using method ⁇ described in Reference (6) .
  • the amino alcohol VI may be reductively alkylated by using a conventional reducing agent, ⁇ uch a ⁇ NaBH 3 CN, NaBH 4 , formic acid, etc. , or by catalytic hydrogenation.
  • the proces ⁇ may be carried out in an inert solvent compatible with the reducing agent, e.g. hydrocarbons, ethers, alcohols, carboxylic acids. Mixtures of more than one solvent may also be employed.
  • the proces ⁇ may suitably be performed at a temperature between about 0 °C and about 100 °C.
  • the ⁇ tarting material VI may be prepared by u ⁇ ing general methods as described in Reference (7) .
  • each group of the starting material ⁇ involved u ⁇ t be compatible with the proces ⁇ in que ⁇ tion or, if nece ⁇ sary protected during one or more reaction steps and then converted to the desired group.
  • Pertinent examples of groups that may be protected are hydroxy, primary amino and secondary amino.
  • the racemic compounds of the general formula I may be resolved u ⁇ ing known method ⁇ , such as various resolving acids. Crystallization of a resolving acid salt of compounds of the general formula I may be effected in any suitable conventional inert organic solvent, and preferably at a temperature from the boiling point of the solvent to -20 °C.
  • Preferred solvent ⁇ are ethanol, 1- propanol, 2-propanol and acetone. Water and mixture ⁇ of solvent ⁇ may al ⁇ o be employed.
  • the separation of racemate ⁇ can also be achieved by various chromatographic techniques, such a ⁇ ⁇ eparation of dia ⁇ tereomeric mixture ⁇ , ⁇ eparation on chiral stationary phases or with chiral counter ion in the mobile phase.
  • the resolution of racemates to the individual optical enantio ers is illustrated further in Example 6 below.
  • the compound ⁇ of the invention are generally characterized by the pharmacological activity stated above, making them useful for counteracting certain physiological abnormalities in a living human or animal body.
  • Effective quantitie ⁇ of a pharmacologically active compound of the invention may be administered to a living human or animal body in any one of various ways, e.g. orally a ⁇ in capsules or tablets, parenterally in the form of sterile solutions, suspensions, emulsions, pellet implantation or by pumps.
  • routes of parenteral administration are intravenous, sublingual, subcutaneous, intramuscular, intraperitoneal, intrader al, intravesical, intraurethral and intranasal administration.
  • Other modes of administration are vaginal, rectal and topical administrations, e.g. in the form of ointments, suppositories, powders, patche ⁇ , sprays and intravaginal devices.
  • Pharmaceutical for ulation ⁇ are usually prepared from a predetermined quantity of one or more of the compounds of the invention.
  • Such formulations may take the form of powders, syrups, suppositories, ointments, solutions, pills, capsules, pellets or tablets, suspensions, emulsions, oil solutions, etc. with or without, but preferably with any one of a large variety of pharmaceutically acceptable vehicles or carriers.
  • the active ingredient When in a mixture with a pharmaceutical vehicle or carrier, the active ingredient usually comprises from about 0.01 to about 75 %, normally about 0.05 to about 15 % by weight of the composition.
  • Carriers such as starch, ⁇ ugar, talc, commonly used synthetic and natural gums, water and the like may be used in such formulation ⁇ .
  • Binder ⁇ such as polyvinylpyrrolidone, and lubricants, ⁇ uch a ⁇ ⁇ odium ⁇ tearate, may be u ⁇ ed to form tablet ⁇ .
  • Di ⁇ integrating agent ⁇ such a ⁇ sodium carbonate may also be included in tablet ⁇ .
  • unit dosages are preferably 2 milligram ⁇ or above, and preferably 10, 20, 50 or 100 milligrams, or even higher depending, of course, upon the subject treated and the particular result desired, as will be apparent to one skilled in the art. Broader ranges would be from 1 to 1000 milligrams per unit dose.
  • the present compounds of formula I may thus be administered in a quantity of 1 to 1000 milligrams, preferred ranges being 2 to 250 milligrams per day per subject or patient divided into one to four dose ⁇ over a suitable period and depending upon the subject and the type of subject being treated.
  • the ⁇ tructure ⁇ of the compounds prepared were confirmed by NMR and elementary or titrimetric analyse ⁇ .
  • the NMR data were recorded u ⁇ ing a BRUKER 250 MHZ instrument.
  • Elementary analyse ⁇ were performed u ⁇ ing a Carlo Erba Elementar Analyzer Mod. 1106. Melting point ⁇ , when given, were determined on a Mettler FF apparatus and are uncorrected.
  • EXAMPLE 3 Sec. butyllithium (1.3 M ⁇ olution in hexane) (0.77 ml, 0.01 mole) i ⁇ added dropwi ⁇ e under nitrogen at -78 °C to a ⁇ tirred mixture of 8 ml of trimethylamine and potassium t- butoxide (1.12 g, 0.01 mole). The mixture is stirred at 0 °C for 1 h and cooled to -78 °C. Thereafter, 35 ml of 0.3 M ⁇ olution of lithium bromide in ether i ⁇ added dropwise. The mixture is stirred for 1 h at 0 °C and cooled to -78 °C, and
  • EXAMPLE 5 ⁇ -Aminomethyl-3-methoxy-2-(1-methylethoxy) - benzenemethanol, (9 g, 0.04 mole) , formic acid (98-100%) (9. g, 0.2 mole) and formaldehyde (37%) (7.2 g, 0.088 mole) is refluxed for 4 h. Then 3.4 ml of concentrated hydrochloric acid i ⁇ added and the formic acid and any exce ⁇ formaldehyd are removed under reduced pre ⁇ ure.
  • the re ⁇ idue is di ⁇ olved in water and made alkaline (pH>ll) by the addition of 25 % • aqueou ⁇ sodium hydroxide, and the mixture is extracted twice with ether and isolated as the hydrogen oxalate.
  • a-[ (Dimethylamino)methyl]-3-methoxy-2-(1-methylethoxy) - benzenemethanol, hydrogen oxalate, m.p. 126 °C. (Compound 5:1 compound 1:4) .
  • EXAMPLE 6 The following examples illustrate the resolution of racemates according to the invention:
  • the race ic 3-chloro- ⁇ -[ (dimethylamino)methyl]-2-(1- methylethoxy)-benzenemethanol (19.35 g, 0.075 mole) and di- 0,0'-p-toluoyl-L-tartaric acid (30.3 g, 0.075 mole) are mixed and the product cry ⁇ tallized from 125 ml of abs. ethanol and 175 ml of water.
  • the mixture is left over night at +4 °C.
  • the precipitated salt is collected by filtration and washed with ethanol-water 1:1.
  • the mother liquors from the two first crystallizations are concentrated together to al o ⁇ t dryness on a rotary evaporator.
  • the residue i ⁇ made alkaline with 2M sodium hydroxide solution and extracted ' with ether.
  • the ether layer is evaporated (14.7 g, 0.057 mole) and crystallized with di- 0,0'-p-toluoyl-D-tartaric acid (21.9 g, 0.057 mole) from 195 ml of 50% ethanol.
  • the product is recrystallized three times from 50% ethanol.
  • the mother liquors from the two first crystallizations are concentrated together to almost dryness on a rotary evaporator. The residue is made alkaline with 2M sodium hydroxide solution and extracted with ether. The ether layer is evaporated.
  • EXAMPLE 7 Manufacturing process for tablets of 20 mg. Model batch for 1000 tablets
  • Sorbitan monooleate 0.5 g Sodium hydroxide 0.2 g Methyl paraben 0.3 g Propyl paraben 0.1 g Ethanol 0.9 g Water to make 100 g
  • the substances are mixed and filled in capsule ⁇ .
  • EXAMPLE 13 20 mg sterile powder to be dissolved in water for injection
  • the substances are dissolved in distilled water.
  • the solution is dispensed in vials and freeze-dried.
  • the Active Compound ⁇ are tho ⁇ e covered by the general formula I above or their addition ⁇ alt ⁇ with pharmaceutically acceptable inorganic or organic acid ⁇ .
  • Water- ⁇ oluble Active Compound ⁇ are ⁇ uch addition ⁇ alt ⁇ or ⁇ alts with a pharmaceutically acceptable inorganic or organic cation.
  • two or more Active Compounds of the invention may be used in combination in the compo ⁇ ition illu ⁇ trated, and also, if desired, in combination with other pharmacologically active agents.
  • the compounds according to the invention are also expected to be effective by instillation in the urinary bladder in doses of 0.0005 to 1 mg/kg body weight.
  • the amount of compound actually administered will be determined by a physician, in the light of the relevant circu stance ⁇ including the condition to be treated, the chosen route of administration, the age, weight and response of the individual patient and the severity of th patient's symptoms, and therefore the above do ⁇ age range ⁇ are not intended to limit the scope of the invention in any way.
  • pharmaceutical formulations embrac compositions and ingredients for both human and veterinary use.
  • the following pharmacological data illustrate the effect of a number of potent and ⁇ elective substances in comparison with a clas ⁇ ical ⁇ -adrenoceptor ⁇ timulating ⁇ ubstance, phenylpropanolamine.
  • test substances were added cumulatively (12 concentrations) until a maximum response was obtained.
  • the result ⁇ are ⁇ ummarized in Table 1 below. Effects on urethral and blood pressure in anaesthetized rabbits Rabbits, weighing 2.5-3 kg, were anaesthetized by pentobarbitone (initially 40 mg/kg i.v. and for maintenance anaesthesia 10 mg/kg, h) .
  • pentobarbitone initially 40 mg/kg i.v. and for maintenance anaesthesia 10 mg/kg, h
  • urethral pressure catheter Dog cath nr 6.
  • the basal urethral pressure was approximately 10 cm H 2 0.
  • the blood pressure was recorded via a catheter (PP50) inserted into a femoral artery.

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Abstract

PCT No. PCT/SE93/00635 Sec. 371 Date Jan. 18, 1995 Sec. 102(e) Date Jan. 18, 1995 PCT Filed Jul. 20, 1993 PCT Pub. No. WO94/02442 PCT Pub. Date Feb. 3, 1994. <IMAGE> (I) Compounds of formula (I) and their physiologically acceptable salts thereof, their use as therapeutical substances, pharmaceutical compositions containing them, and methods for preparing the compounds.

Description

PHARMACOLOGICALLY ACTIVE α-fTERTIARY-AMINOMETHYL1- BENZENEMETHANOL DERIVATIVES
FIELD OF THE INVENTION The present invention relates to novel α-(tertiary- aminomethyl) -benzenemethanol derivatives having pharmacological properties, and to processes for their preparation. The invention also relates to pharmaceutical compositions containing these derivatives and methods of treatment therewith.
BACKGROUND OF THE INVENTION Urinary incontinence is a very common disorder in both men and women. Large or smaller amounts of urine are involuntarily expelled from the bladder. There are two main types of urinary incontinence, i.e. urge incontinence and stress incontinence. Very few drugs are available for treatment of the latter type and they have been found to have low efficacy and significant side-effects.
PRIOR ART DD-A-210 031 discloses a process for the preparation of pharmacologically active l-aryl-2-aminoethanols. Specifically described are phenylethanolamines which are either unsubstituted or mono-substituted in phenyl ring positions 2 or 4 , or tri-substituted in positions 3, 4 and 5. EP-A-103 830 discloses growth-promoting phenylethanolamine derivatives. No compounds di-substituted in positions 2 and 3 of the phenyl ring are specifically described.
EP-A-213 108 discloses pharmaceutical formulations containing an α- and/or β-sympathicomimetic agent in the form of a phenylethanolamine derivative. The only specific compound mentioned is 1- (3 ' -hydroxyphenyl) -2-aminoethanol .
US-A-4 , 349, 549 discloses hypertensively active ω-aryl-ω- hydroxyalkyl-spiropiperidine heterocycles. SUMMARY OF THE INVENTION
According to the present invention it has been found that a novel class of 2 , 3-disubstituted-α- (tertiary-amino ethyl) - benzenemethanol derivatives have properties making them suitable for the treatment of disorders related to urinary incontinence, and which novel derivatives have higher efficac and lower side-effects than the prior art drugs.
In one aspect, he present invention therefore provides novel compounds which may be represented by the general formula I:
wherein R is selected from alkyl, alkoxy, alkenyloxy, arylalkox alkylthio and alkenylthio;
R2 is selected from halogen, hydroxy, alkyl, alkoxy, alkenyloxy, alkylthio, alkenylthio, alkylamino, trifluoromethyl, cyano, nitro, alkylsulfinyl, alkylsulfonyl and acyl;
R3 and R4 either independently represent alkyl or alkenyl, or R3 and R4 are interconnected to form a heterocyclic system with the nitrogen atom, optionally containing one or more additional heteroatoms; and physiologically acceptable salts thereof.
In another aspect, the present invention provides the compounds having the general formula I above for therapeutica use, especially as urination controlling agents.
In still another aspect, the present invention provides method of treating a living body suffering from a disorder related to urinary incontinence, which method comprises the step of administering to the said living body an effective amount of a compound having the general formula I above.
In yet another aspect, the present invention provides a pharmaceutical composition comprising one or more compounds o the general formula I above as the active ingredient, preferably together with a pharmaceutically acceptable carrie and, if desired, other pharmacologically active agents. In another aspect, the present invention provides the us of the compounds having the general formula I above for the manufacture of a medicament for the treatment of urination control disorders. In still another aspect, the present invention provides processes for preparing compounds having the general formula above.
DETAILED DESCRIPTION OF THE INVENTION In the compounds having the general formula I as defined above, the term alkyl, separately and in combinations such as alkylthio, alkylamino, alkylsulfinyl and alkylsulfonyl, iε meant to include straight and branched, saturated hydrocarbon groups. Exemplary alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, n-pentyl, n-hexyl. The term alkenyl, separately and in combinations such as alkenyloxy and alkenylthio, is meant to include straight and branched hydrocarbon groups containing one or more unsaturations. Exemplary alkenyl groups are ethenyl, propenyl, butenyl, pentenyl, hexenyl, methylpropenyl, ethylbutenyl. The term alkoxy, separately and in combinations such as arylalkoxy, is meant to include straight and branched, saturated alkoxy groups. Exemplary alkoxy groups are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, n-pentyloxy, n-hexyloxy. The term alkenyloxy is meant to include straight and branched alkenyloxy groups containing one or more unsaturations. Exemplary alkenyloxy groups are ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, methylpropenyloxy, ethylbutenyloxy. The term aryl, separately and in combinations, is meant to include aromatic systems that are either heterocyclic or only carbon-containing. Exemplary of heterocyclic aromatic systems are thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, isobenzofuran, benzothiazole, benzothiophene, indole, isoindole, oxadiazole, benzoxazole. Exemplary of only carbon-containing aromatic systems are phenyl and naphthyl . The term acyl is meant to include straight, branched or cyclic, saturated, unsaturated or aromatic acyl groups.
Exemplary acyl groups are formyl, acetyl, propionyl, butyryl, succinyl, crotonyl, cinna oyl, benzoyl. The term halogen is meant to include fluoro, chloro, bromo and iodo.
R1 is preferably selected from alkoxy and lower alkylthi having 1-5 carbon atoms.
R2 is preferably selected from halogen, alkoxy, alkylthio, trifluoromethyl, cyano, nitro, lower alkylsulfinyl, lower alkylsulfonyl and lower acyl; lower alkyl, lower acyl and lower alkoxy preferably containing 1-5 carbon atoms.
R3 and R4 are preferably, independently, selected from the group consisting of lower alkyl having 1-5 carbon atoms, or R3 and R4 , together with the nitrogen atom, form a 5- or 6 membered heterocyclic ring such as pyrrolidine, piperidine, morpholine.
The general formula I includes the enantiomeric and racemic forms. The compounds of formula I which contain salt- forming basic nitrogen atoms may also be in the form of salts suitable for pharmacological use.
The following specific compounds are preferred: α-[ (dimethylamino)methyl]-2-(1-methylethoxy)-3-methyl- benzenemethanol; 3-chloro-α-[ (dimethylamino) ethyl]-2-ethoxy-benzenemethanol; α-[ (diethylamino)methyl]-3-methoxy-2-(1-methylethoxy) - benzenemethanol; α-[ (dimethylamino)methyl]-3-methoxy-2-(1-methylethoxy) - benzenemethanol ; α-[ (dimethylamino)methyl]-3-methoxy-2-(2-propenyloxy) - benzenemethanol;
3-methoxy-2-(l-methylethoxy) -α-pyrrolidinomethyl- benzenemethanol;
3-methoxy-2-(2-propenyloxy) -α-pyrrolidinomethyl- benzenemethanol;
3-chloro-2- (1-methylethoxy) -α-pyrrolidinomethyl- benzenemethanol ; 3-chloro- -[ (dimethylamino) ethyl]-2-(1-methylethoxy) - benzenemethanol;
3-chloro-α-[ (N-ethyl-N-methylamino)methyl]-2- (1-methylethoxy) - benzenemethanol; 3-chloro-α-[ (diethylamino)methyl]-2- (1-methylethoxy) - benzenemethanol; α-[ (dimethylamino)methyl]-2- (1-methylethoxy) -3-nitro- benzenemethanol;
3-chloro-α-f (dimethylamino)methyl]-2- (1-methylethylthio) - benzenemethanol; α-[ (dimethylamino)methyl]-3-methoxy-2-(1-methylethylthio) - benzenemethanol;
3-chloro-α-[ (dimethylamino)methyl]-2-(methylthio) - benzenemethanol; -[ (dimethylamino)methyl]-3-methoxy-2-(methylthio) - benzenemethanol; a-[ (dimethylamino)methyl]-2-ethylthio-3-methoxy- benzenemethanol ; -[ (dimethylamino)methyl]-2-(1-methylethoxy) -3-methylthio- benzenemethanol; α-[ (dimethylamino)methyl]-2-(1-methylethoxy) -3-methylsulfonyl- benzenemethanol; -[ (dimethylamino)methyl]-2-(1-methylethoxy) -3-methylsulfinyl- benzenemethanol . The compounds having the general formula I may be prepared by conventional methods, and especially according to the following methods a) to e) .
Method a:
A compound of the general formula II,
wherein R1 and R2 are as previously defined, is reacted with an amine having the general formula HNR3R4 , wherein R3 and R4 are as previously defined; to form a compound of the general formula I. Method b:
A compound of the general formula III,
wherein R1, R2 , R3 and R4 are as previously defined, is reduced to a compound of the general formula I. Method c:
A compound having the general formula IV,
wherein R1 and R2 are as previously defined, is reacted with reactive derivative of a -tertiary amine NR3R4R5, wherein R3, R4 and R5 independently are lower alkyl or R3 and R4 together form a saturated ring system, to form a compound having the general formula I. Method d:
A compound of the general formula V,
wherein R1, R , R3 and R4 are as previouεly defined, and Q iε oxygen or sulfur, iε reduced to a compound of the general formula I. Method e:
A compound of the general formula VI,
wherein R1 and R2 are as previously defined, is reductively alkylated with an aldehyde to form a compound of the general formula I. Method a) above (which is illustrated further in Example 1 below) may be carried out by mixing the reagents, or the reagents may be dissolved or suspended in an inert solvent such as an alcohol, e.g. ethanol, water, dimethyl sulfoxide, acetonitrile etc. Mixtures of more than one solvent may be employed. A suitable temperature range for the reaction is between about 20 °C and about 150 °C, usually between about 20 °C and about 100 °C. The resulting product may be isolated by conventional procedures. The starting material of formula II may be prepared from compounds of the general formula IV by methods described in Reference (1) in the list of References at the end of the description. The crude epoxide II is preferably directly reacted with the desired amine. In method b) (which is further illustrated in Example 2 below) the amino ketone III may be reduced by using a conventional reducing agent, such as LiAlH4 BH3-THF, NaBH4 etc., or by catalytic hydrogenation. The process may be carried out in an inert solvent compatible with the reducing agent, e.g. hydrocarbons, ethers, alcohols, carboxylic acids. Mixtures of more than one solvent may also be employed. A εuitable temperature range for carrying out the process is between about 20 °C and about 100 °C.
The starting material III may be prepared by using general methods as described in Reference (2) . Method c) (which is illustrated further in Example 3 below) may be carried out in an excess of the non- activated amine NR3R4R5 or in an inert solvent medium, usually at -70 °C or below. The reactive derivative of the amine may, for example, be LiCH2NR3R , wherein R3 and R4 are lower alkyl groups or together form a εaturated ring system.
The reactive amine derivatives can be prepared according to the method described in Reference (3) or from (n-C4Hg)3SnCH2NR3R4 described in Reference (4) . The starting amines, such as CH3NR3R4' are known compounds. Compounds having the general formula IV are known co poundε or can be prepared by conventional methodε aε described in Reference (5) .
In method d) (which is illustrated further in Example 4 below) the reduction of the tertiary amide (formula V, Q=0) or tertiary thioamide (formula V, Q=S) with a reducing agent to the compound of the general formula I can be performed by using conventional reducing agentε, including LiAlH4, BH3-S(CH3)2, NaBH4~CoCl2, etc. The process may be carried out in an inert organic solvent compatible with the reducing agent, suitably at a temperature between about 20 °C and about 100 °C. This reduction may also be performed by catalytic hydrogenation in per se known manner. The starting material of the general formula V may be prepared from α-hydroxybenzeneacetic acid derivatives by per se known methods or be prepared from compounds of the general formula IV by using methodε described in Reference (6) . In method e) (which is illustrated further in Example 5 below) the amino alcohol VI may be reductively alkylated by using a conventional reducing agent, εuch aε NaBH3CN, NaBH4 , formic acid, etc. , or by catalytic hydrogenation. The procesε may be carried out in an inert solvent compatible with the reducing agent, e.g. hydrocarbons, ethers, alcohols, carboxylic acids. Mixtures of more than one solvent may also be employed. The procesε may suitably be performed at a temperature between about 0 °C and about 100 °C. The εtarting material VI may be prepared by uεing general methods as described in Reference (7) .
It is, of course, also possible to prepare compounds having the general formula I above from other co poundε within the definition of this general formula, using procedureε known per se. As examples of such tranεformationε the following may be mentioned: Free hydroxy groupε are, e.g., obtained by removal of acyl groups from carboxylic esterε. Lower alkylεulfinyl and lower alkylsulfonyl groups are, e.g. , obtained by oxidation of methylthio groups. Primary and secondary amines can be acylated to amides and alkylated to corresponding amineε, and amideε can be reduced to correεponding amines.
In synthesizing compounds having the general formula I by any of the methods mentioned above, each group of the starting materialε involved uεt be compatible with the procesε in queεtion or, if neceεsary protected during one or more reaction steps and then converted to the desired group. Pertinent examples of groups that may be protected are hydroxy, primary amino and secondary amino.
The racemic compounds of the general formula I may be resolved uεing known methodε, such as various resolving acids. Crystallization of a resolving acid salt of compounds of the general formula I may be effected in any suitable conventional inert organic solvent, and preferably at a temperature from the boiling point of the solvent to -20 °C. Preferred solventε are ethanol, 1- propanol, 2-propanol and acetone. Water and mixtureε of solventε may alεo be employed. The separation of racemateε can also be achieved by various chromatographic techniques, such aε εeparation of diaεtereomeric mixtureε, εeparation on chiral stationary phases or with chiral counter ion in the mobile phase. The resolution of racemates to the individual optical enantio ers is illustrated further in Example 6 below.
All the above described methods, including the resolution of racemates, may optionally be carried out in the presence of a catalyst known to be useful therein.
The compoundε of the invention are generally characterized by the pharmacological activity stated above, making them useful for counteracting certain physiological abnormalities in a living human or animal body. Effective quantitieε of a pharmacologically active compound of the invention may be administered to a living human or animal body in any one of various ways, e.g. orally aε in capsules or tablets, parenterally in the form of sterile solutions, suspensions, emulsions, pellet implantation or by pumps. Among routes of parenteral administration are intravenous, sublingual, subcutaneous, intramuscular, intraperitoneal, intrader al, intravesical, intraurethral and intranasal administration. Other modes of administration are vaginal, rectal and topical administrations, e.g. in the form of ointments, suppositories, powders, patcheε, sprays and intravaginal devices.
Pharmaceutical for ulationε are usually prepared from a predetermined quantity of one or more of the compounds of the invention. Such formulations may take the form of powders, syrups, suppositories, ointments, solutions, pills, capsules, pellets or tablets, suspensions, emulsions, oil solutions, etc. with or without, but preferably with any one of a large variety of pharmaceutically acceptable vehicles or carriers.
When in a mixture with a pharmaceutical vehicle or carrier, the active ingredient usually comprises from about 0.01 to about 75 %, normally about 0.05 to about 15 % by weight of the composition. Carriers such as starch, εugar, talc, commonly used synthetic and natural gums, water and the like may be used in such formulationε. Binderε, such as polyvinylpyrrolidone, and lubricants, εuch aε εodium εtearate, may be uεed to form tabletε. Diεintegrating agentε such aε sodium carbonate may also be included in tabletε.
Although relatively small quantities of the active materials of the invention, even aε low as 0.5 milligram, may be used in cases of administration to subjects having a relatively low body weight, unit dosages are preferably 2 milligramε or above, and preferably 10, 20, 50 or 100 milligrams, or even higher depending, of course, upon the subject treated and the particular result desired, as will be apparent to one skilled in the art. Broader ranges would be from 1 to 1000 milligrams per unit dose.
The present compounds of formula I may thus be administered in a quantity of 1 to 1000 milligrams, preferred ranges being 2 to 250 milligrams per day per subject or patient divided into one to four doseε over a suitable period and depending upon the subject and the type of subject being treated.
EXAMPLES The following examples are intended to illustrate but no to limit the scope of the invention, the compounds specifically named, however, being of particular interest for the intended purposeε. These compounds are designated by numbers in the Examples where their preparations are describe and where their εyεtematic nameε are given. The compoundε are later on referred to by a number code, a:b, where "a" means the number of the example, in which the preparation of the compound in question is described, and "b" refers to the orde of the compoundε prepared according to that example. Thus, compound 1:2 means the second compound prepared according to Example 1.
The εtructureε of the compounds prepared were confirmed by NMR and elementary or titrimetric analyseε. The NMR data were recorded uεing a BRUKER 250 MHZ instrument. Elementary analyseε were performed uεing a Carlo Erba Elementar Analyzer Mod. 1106. Melting pointε, when given, were determined on a Mettler FF apparatus and are uncorrected.
EXAMPLE 1 2-[3-methyl-2- (1-methylethoxy)phenyl]oxirane (1.92 g, 0.01 mole) iε added to dimethylamine (1.35 g, 0.03 mole) at
-15 °C in a pressure vesεel and iε allowed to warm up to room temperature with εtirring during 8 h. It is then kept at ambient temperature for 40 h. After cooling, the exceεε of th amine iε evaporated and purified by chromatography on εilica gel using toluene:methanol (containing 20% by weight of ammonia), 9:1. The desired fraction iε, if necessary, isolate as a suitable salt. 1. -[ (Dimethylamino) ethyl]-2-(1-methylethoxy)-3-methyl- benzenemethanol, hydrochloride, m.p. 104 °C.
In esεentially the εame manner the following compoundε are obtained from the corresponding starting materials:
2. 3-Chloro-α-[ (dimethylamino)methyl]-2-ethoxy- benzenemethanol, hydrochloride, m.p. 135 °C.
3. α-[ (Diethylamino)methyl]-3-methoxy-2-(l- methylethoxy)-benzenemethanol, hydrogen oxalate, m.p. 95 °C.
4. α-[ (Dimethylamino) ethyl]-3-methoxy-2-(1- methylethoxy)-benzenemethanol, hydrogen oxalate, m.p. 126 °C.
5. 3-Methoxy-2-(l-methylethoxy)-α-pyrrolidinomethyl- benzenemethanol, hydrochloride, m.p. 213 °C.
6. 3-Methoxy-2-(l-methylethoxy)- -morpholinomethyl- benzenemethanol, hydrochloride, m.p. 160 °C.
7. 3-Chloro-2-(1-methylethoxy)-α-pyrrolidinomethyl- benzenemethanol, hydrogen oxalate, m.p. 128 °C.
8. 3-Methoxy-2-(1-propenyloxy)-α-pyrrolidinomethyl- benzenemethanol, hydrogen oxalate, m.p. 103 °C. 9. 3-Chloro-c--[ (dimethylamino)methyl]-2-(1- methylethoxy)-benzenemethanol, hydrochloride, m.p. 120 °C.
10. 3-Chloro-α-[ (diethylamino)methyl]-2-(1-methylethoxy)- benzenemethanol, hydrogen oxalate, m.p. 91 °C.
11. 3-Chloro-α-[ (N-ethyl-N-methylamino)methyl]-2-(1- methylethoxy)-benzenemethanol, hydrochloride, m.p. 127 °C.
12. -[ (Dimethylamino)methyl]-2-(1-methylethoxy)-3-nitro- benzenemethanol, hydrochloride, m.p. 133 °C.
13. 3-Chloro-α-[ (dimethylamino)methyl]-2-(1- methylethylthio)-benzenemethanol, hydrochloride, m.p. 141 °C.
14. -[ (Dimethylamino)methyl]-3-methoxy-2-(1- methylethylthio)-benzenemethanol, hydrochloride, m.p. 141 °C. 15. -[ (Dimethylamino)methyl]-3-methoxy-2-(2- propenyloxy) -benzenemethanol, hydrogen oxalate, m.p. 80 °C.
16. α-[ (Dimethylamino)methyl]-2, 3-di- (1-methylethoxy) - benzenemethanol, base, m.p. 44 °C. 17. α-[ (Dimethylamino)methyl]-3-methoxy-2-[ (3-methyl-2- butenyl) oxy]-benzenemethanol (oil) .
EXAMPLE 2 To a solution of 2-(dimethylamino) -1-(3-chloro-2- ethoxyphenyl) ethanone, hydrochloride (2.25 g, 0.0081 mole) in methanol (50 ml) and water (15 ml) iε added with stirring and cooling (-5 °C) sodium borohydride (0.65 g, 0.0171 mole) in portions. After stirring at ambient temperature for 2 h, 10 m of 2 N hydrochloric acid is added. The mixture is concentrate under reduced presεure to remove methanol, diluted with water and made alkaline with concentrated ammonium hydroxide. After extraction of the mixture with ether, the ether layer iε drie over anhydrouε sodium sulfate. The desired product is isolate aε the hydrochloride (1) below and recryεtallized from 2- propanol:ether. 1. 3-Chloro-α-[ (dimethylamino)methyl]-2-ethoxy- benzenemethanol, hydrochloride, m.p. 135 °C. (Compound 2:1 = compound 1:2) .
In essentially the same manner the following compound iε obtained from the correεponding εtarting material: 2. 3-Chloro- -[ (dimethylamino)methyl]-2- (1-methylethoxy)- benzenemethanol, hydrochloride, m.p. 120 °C. (Compound 2:2 = compound 1:9) .
EXAMPLE 3 Sec. butyllithium (1.3 M εolution in hexane) (0.77 ml, 0.01 mole) iε added dropwiεe under nitrogen at -78 °C to a εtirred mixture of 8 ml of trimethylamine and potassium t- butoxide (1.12 g, 0.01 mole). The mixture is stirred at 0 °C for 1 h and cooled to -78 °C. Thereafter, 35 ml of 0.3 M εolution of lithium bromide in ether iε added dropwise. The mixture is stirred for 1 h at 0 °C and cooled to -78 °C, and
3-methoxy-2- (1-methylethoxy) -benzaldehyde (1.55 g, 0.008 mole in 10 ml of ether iε added at -78 °C. The reaction mixture is allowed to stay at room temperature over night and poured in ice-water, acidified to pH 3 and extracted twice with ether. The ether extract iε washed with water and dried over anhydrous sodium sulfate. The desired product is isolated as the oxalate (1) below and recrystallized from propanol:ether.
1. α-[ (Dimethylamino)methyl]-3-methoxy-2-(1- ethylethoxy) -benzenemethanol, hydrogen oxalate, m.p. 126 °C. (Compound 3:1 = compound 1:4) .
In essentially the same manner the following compound is obtained from the corresponding starting material:
2. 3-Chloro- -[ (dimethylamino) ethyl]-2-(1- ethylethoxy) -benzenemethanol, hydrochloride, m.p. 120 °C. (Compound 3:2 = compound 1:9).
EXAMPLE 4 A solution of N,N-dimethyl-c_-hydroxy-3-methoxy-2-(1- methylethoxy)-benzeneethanethioamide (2.87 g, 0.01 mole) in ml of anhydrous THF is added to a stirred suspension of lithium aluminium hydride (1.5 g) in 15 ml of -anhydrous THF under a nitrogen atmosphere. The mixture iε refluxed for 18 and cooled. Deεtruction of the excess of lithium aluminium hydride is completed by cautious dropwise addition of 1.5 ml of water followed by 2.3 ml of 15 % aqueous sodium hydroxide εolution and εubεequent addition of 4.5 ml of water. Stirrin is continued until a granular white precipitate is formed. Filtration yields a clear solution. THF is removed under reduced preεεure and the residue is dissolved in ether. The desired product iε iεolated aε hydrogen oxalate and recrystallized from ethyl acetate. -[ (Dimethylamino)methyl]-3-methoxy-2- (1-methylethoxy) - benzenemethanol, hydrogen oxalate, m.p. 126 °C. (Compound 4: = compound 1:4) .
EXAMPLE 5 α-Aminomethyl-3-methoxy-2-(1-methylethoxy) - benzenemethanol, (9 g, 0.04 mole) , formic acid (98-100%) (9. g, 0.2 mole) and formaldehyde (37%) (7.2 g, 0.088 mole) is refluxed for 4 h. Then 3.4 ml of concentrated hydrochloric acid iε added and the formic acid and any exceεε formaldehyd are removed under reduced preεεure. The reεidue is diεεolved in water and made alkaline (pH>ll) by the addition of 25 % • aqueouε sodium hydroxide, and the mixture is extracted twice with ether and isolated as the hydrogen oxalate. a-[ (Dimethylamino)methyl]-3-methoxy-2-(1-methylethoxy) - benzenemethanol, hydrogen oxalate, m.p. 126 °C. (Compound 5:1 = compound 1:4) .
EXAMPLE 6 The following examples illustrate the resolution of racemates according to the invention: The race ic 3-chloro-α-[ (dimethylamino)methyl]-2-(1- methylethoxy)-benzenemethanol (19.35 g, 0.075 mole) and di- 0,0'-p-toluoyl-L-tartaric acid (30.3 g, 0.075 mole) are mixed and the product cryεtallized from 125 ml of abs. ethanol and 175 ml of water. The mixture is left over night at +4 °C. The precipitated salt is collected by filtration and washed with ethanol-water 1:1. The product, 42.71 g, is recrystallized twice from 50 % ethanol and converted via the base to the hydrochloride of (-) -3-chloro- -[ (dimethylamino)methyl]-2-(1- methylethoxy) -benzenemethanol. Yield 6.6 g. M.p. 99 °C. [α]D 2 = -52.4° (C = 1 % in ethanol) . (Compound 6:1)
The mother liquors from the two first crystallizations are concentrated together to al oεt dryness on a rotary evaporator. The residue iε made alkaline with 2M sodium hydroxide solution and extracted' with ether. The ether layer is evaporated (14.7 g, 0.057 mole) and crystallized with di- 0,0'-p-toluoyl-D-tartaric acid (21.9 g, 0.057 mole) from 195 ml of 50% ethanol. The product is recrystallized three times from 50% ethanol. The product (19.5 g) is converted via the base to the hydrochloride of (+) -3-chloro-α- [ (dimethylamino)methyl]-2-(1-methylethoxy)-benzenemethanol. Yield 7.2 g. M.p. 98 °C. [α]D 25 = +50.9°. (C = 1% in ethanol) . (Compound 6:2)
The racemic a-[ (dimethylamino)methyl]-3-methoxy-2-(1- methylethoxy) -benzenemethanol (253.0 g, 1 mole) and di-0,0'-p toluoyl-D-tartaric acid (386.3 g, 1 mole) are mixed and the product cryεtallized from ethanol-water 6:4 (765 ml) . After 2 hours at room temperature, the temperature iε gradually decreaεed to 10 °C. The precipitated salt is collected by filtration and waεhed with ethanol-water 1:1 (2 x 60 ml) and ethanol-water 6:4 (2 x 60 ml) and dried in vacuum. The product, 205 g, is recrystallized twice from ethanol-water 6:4, and converted to the base, (+) -α-[ (dimethylamino)methyl] 3-methoxy-2-(l-methylethoxy) -benzenemethanol. Yield 51 g. M.p 49.2 °C. [ ]D 25 = +52° (C = 1% in ethanol). (Compound 6:3) The mother liquors from the two first crystallizations are concentrated together to almost dryness on a rotary evaporator. The residue is made alkaline with 2M sodium hydroxide solution and extracted with ether. The ether layer is evaporated. 87 g (0.343 mole) of the base are crystallized with di-0,0-p-toluoyl-L-tartaric acid (132.8 g, 0.343 mole) from ethanol:water 6:4, 231 ml. The precipitated salt is collected by filtration and washed with ethanol:water 1:1 (2 20 ml) and ethanol:water 6:4 (2 x 20 ml) and dried in vacuum. The product, 70.3 g, iε recrystallized twice from ethanol:water 6:4 and converted to the base, (-) -α-[ (dimethylamino)methyl]-3-methoxy-2-(1-methylethoxy) - benzenemethanol. Yield 17.5 g. M.p. 49.1 °C. [α]D 25 = -52° (C = 1 % in ethanol). (Compound 6:4).
EXAMPLE 7 Manufacturing process for tablets of 20 mg. Model batch for 1000 tablets
I Active Compound, mesh* 70 20 g Lactoεum, Ph. Nord 210 g
Amylum maidiε, Ph. Nord 75 g
II Kollidon 25 B.A.S.F. 3.5 g Aqua purificata q.s.
III Talcum, Ph. Nord 15 g Magnesii εtearaε, Ph. Nord. 1.5 g
Weight of 1000 tablets 325 g
Weight of 1 tablet: 325 mg
*The mesh standard is according to the international εyεtem o code DIN 4189/1968. Punch: 10.5 mm round, flat εcored, bevel-edged.
Mix the screened εubεtanceε I thoroughly and then moiste with II, whereupon the mixture iε granulated through a stainlesε sieve No. 10 (mesh 25) . Dry the granulate in an ove at a maximum temperature of 40 °C, then repeat sieving throug sieve No. 10. Add the substances under III and mix thoroughly.
Punch tablets with a gross weight of about 325 mg. EXAMPLE 8 Suspension for injection 20 mg/ l
Active compound, mesh 100 20 mg
Sodium Chloride 8 mg
Carboxy methylcellulose 1 mg Benzyl alcohol 1 mg
Distilled water to make 1 ml
EXAMPLE 9
Oral suspension 5 mg/ml Active compound, mesh 100 20 mg
Sorbitσl 600 mg
Flavouring compound q.s.
Colour q.s.
Water to make 1 ml
EXAMPLE 10 Suppoεitoria of 25 mg
Active compound 25 mg
Cocoa butter q.ε.
EXAMPLE 11
Ointment 2
Active compound 2 g
Triethanolamine 1 g Glycerol 7 g
Cetanol 2.5 g
Lanolin 2.5 g
Stearic acid 20 g
Sorbitan monooleate 0.5 g Sodium hydroxide 0.2 g Methyl paraben 0.3 g Propyl paraben 0.1 g Ethanol 0.9 g Water to make 100 g
EXAMPLE 12
Capsules of 10 mg
Active compound 10 mg Magnesium stearate 2 mg Talcum 188 mg
The substances are mixed and filled in capsuleε.
EXAMPLE 13 20 mg sterile powder to be dissolved in water for injection
Water-soluble Active Compound 10 mg Sodium chloride 4 mg Methyl paraben 0.7 mg Propyl paraben 0.3 mg
The substances are dissolved in distilled water. The solution is dispensed in vials and freeze-dried.
EXAMPLE 14 Injectable solution 20 mg/ml
Water-εoluble Active Compound 20 mg
Ascorbic acid 1 mg
Sodium bisulfite 1 mg
Sodium chloride 6 mg
Methyl paraben 0.7 mg
Propyl paraben 0.3 mg
Distilled water to make 1 ml
In the foregoing Examples 8-14 relating to compoεitionε, the Active Compoundε are thoεe covered by the general formula I above or their addition εaltε with pharmaceutically acceptable inorganic or organic acidε. Water-εoluble Active Compoundε are εuch addition εaltε or εalts with a pharmaceutically acceptable inorganic or organic cation. Also it is to be noted that two or more Active Compounds of the invention may be used in combination in the compoεition illuεtrated, and also, if desired, in combination with other pharmacologically active agents.
The compounds according to the invention are also expected to be effective by instillation in the urinary bladder in doses of 0.0005 to 1 mg/kg body weight. However, i will be understood that the amount of compound actually administered will be determined by a physician, in the light of the relevant circu stanceε including the condition to be treated, the chosen route of administration, the age, weight and response of the individual patient and the severity of th patient's symptoms, and therefore the above doεage rangeε are not intended to limit the scope of the invention in any way. As used herein the terms "pharmaceutical formulations" embrac compositions and ingredients for both human and veterinary use.
The following pharmacological data illustrate the effect of a number of potent and εelective substances in comparison with a clasεical α-adrenoceptor εtimulating εubstance, phenylpropanolamine.
Effects on the isolated rabbit urethra and portal vein Female rabbits weighing 2.5 - 3.0 kg were sacrificed and exsanguinated. The urethra and portal vein were dissected out and suspended in organ baths containing oxygenated Krebs solution at 37 °C. Two rings of urethra (4 mm broad) and two longitudinal εtripε of the portal vein were uεed. The baεal tenεion waε adjuεted to about 10 mN after an equilibration time of 60 minutes. Isometric tension was recorded via a forc transducer (Statham FT03) and registered on a Grasε polygraph model 7.
Submaximum concentrationε of noradrenaline (6 x 10'5 M) were used to achieve reference contractionε.
The test substances were added cumulatively (12 concentrations) until a maximum response was obtained. The resultε are εummarized in Table 1 below. Effects on urethral and blood pressure in anaesthetized rabbits Rabbits, weighing 2.5-3 kg, were anaesthetized by pentobarbitone (initially 40 mg/kg i.v. and for maintenance anaesthesia 10 mg/kg, h) . For recording of urethral pressure catheter (Dog cath nr 6.) was inserted into the urethra and placed at the point of highest presεure. The basal urethral pressure was approximately 10 cm H20. The blood pressure was recorded via a catheter (PP50) inserted into a femoral artery. Substances were injected intravenously into a catheter in a femoral vein. The continuous intravenous infusion of pentobarbitone kept the depth of anaesthesia at a constant level throughout the experiment. Three consecutive noradrenaline injections (0.025 μg/kg i.v.) were given initially to constitute reference reεponses. Repeated intravenouε injectionε of different doεeε of the same test compound were given in a randomized manner. The resultε are summarized in Table 1 below. The data clearly show that the compounds described have a very high selectivity for the urethra in comparison with their effects on blood veεsels and blood presεure. In other pharmacological experimentε (not described here) it was also shown that the described compound had no or minimal effect on other organs, such as for example the urinary bladder, central nervous system, intestine, vas deferens etc.
Table 1
l->
References: 1. A.S. Rao, et al., Tetrahedron .39. (1983), 2323; D.S. Matteson, Tetrahedron Lett. 21_ (1986) , 795, and references cited therein. 2. Houben-Weyl: Methoden der organischen Chemie, Ketone III 7/2c, 2253, and references cited therein.
3. H. Ahlbrecht, et al. , Tetrahedron Lett. 2_4 (1984), 1353.
4. J.P. Quintard, et al., Syntheεis (1984), 495. 5. Houben-Weyl: Methoden der organischen Chemie,
Aldehyde E3, 767, Sauerstoffverbindungen II 7/1, 537, and references cited therein.
6. P. Beak, Chemical Reviewε 7_8 (1978), 275; Chemical Reviewε 8_4 (1984) , 471, and references cited therein. 7. Comprehensive Organic Chemistry (1979), Vol. 2, 94, and references cited therein.

Claims

CLAIMS 1. A compound of the general formula I
wherein
R1 is selected from alkyl, alkoxy, alkenyloxy, arylalkoxy, alkylthio and alkenylthio;
R2 is selected from halogen, hydroxy, alkyl, alkoxy, alkenyloxy, alkylthio, alkenylthio, alkylamino,
trifluoromethyl, cyano, nitro, alkylsulfinyl, alkylsulfonyl and acyl;
R3 and R4 either independently represent alkyl or
alkenyl, or R3 and R4 are interconnected to form a
heterocyclic system with the nitrogen atom, optionally
containing one or more additional heteroatoms;
and physiologically acceptable salts thereof.
2. A compound according to claim 1, wherein
R1 is selected from alkoxy and lower alkylthio having 1-5 carbon atoms,
R2 is selected from halogen, alkoxy, alkylthio,
trifluoromethyl, cyano, nitro, lower alkylsulfinyl, lower alkylsulfonyl and lower acyl, lower alkyl, lower acyl and lower alkoxy containing 1-5 carbon atoms, and
R3 and R4 are independently selected from lower alkyl having 1-5 carbon atoms, or R3 and R4 , together with the nitrogen atom, form a 5- or 6-membered heterocyclic ring. 3. A compound according to claim 1 selected from:
α-[(dimethylamino)methyl]-2-(1-methylethoxy)-3-methyl-benzenemethanol;
3-chloro-α-[(dimethylamino)methyl]-2-ethoxy-benzenemethanol; α-[(diethylamino)methyl]-3-methoxy-2-(1-methylethoxy)-benzenemethanol;
α-[(dimethylamino)methyl]-3-methoxy-2-(1-methylethoxy)-benzenemethanol;
α-[(dimethylamino)methyl]-3-methoxy-2-(2-propenyloxy)-benzenemethanol;
3-methoxy-2-(1-methylethoxy)-α-pyrrolidinomethyl-benzenemethanol;
3-methoxy-2-(2-propenyloxy)-α-pyrrolidinomethyl-benzenemethanol;
3-chloro-2-(1-methylethoxy)-α-pyrrolidinomethyl-benzenemethanol;
3-chloro-α-[(dimethylamino)methyl]-2-(1-methylethoxy)-benzenemethanol;
3-chloro-α-[(N-ethyl-N-methylamino)methyl]-2-(1-methylethoxy)benzenemethanol;
3-chloro-α-[(diethylamino)methyl]-2-(1-methylethoxy)-benzenemethanol;
α-[(dimethylamino)methyl]-2-(1-methylethoxy)-3-nitro-benzenemethanol;
3-chloro-α-[(dimethylamino)methyl]-2-(1-methylethylthio)-benzenemethanol;
α-[(dimethylamino)methyl]-3-methoxy-2-(1-methylethylthio)-benzenemethanol;
3-chloro-α-[(dimethylamino)methyl]-2-(methylthio)-benzenemethanol;
α-[(dimethylamino)methyl]-3-methoxy-2-(methylthio)-benzenemethanol;
α-[(dimethylamino)methyl]-2-ethylthio-3-methoxy-benzenemethanol;
α-[(dimethylamino)methyl]-2-(1-methylethoxy)-3-methylthio-benzenemethanol;
α-[(dimethylamino)methyl]-2-(1-methylethoxy)-3-methylsulfonylbenzenemethanol;
α-[(dimethylamino)methyl]-2-(1-methylethoxy)-3-methylsulfinylbenzenemethanol;
and physiologically acceptable salts thereof.
4. A compound according to any one of claims 1 to 3 for use as a therapeutically active substance.
5. A method of treating a living body suffering from a disorder related to urinary incontinence, which method comprises the step of administering to said living body an effective amount of a compound according to any one of claims 1 to 3.
6. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 3,
optionally together with a pharmaceutically acceptable carrier.
7. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment of urination control disorders.
8. A method for preparing a compound of formula I as defined in claim 1, which comprises
a) reacting a compound of the general formula II,
wherein R1 and R2 are as defined in claim 1, with an amine having the general formula HNR3R4, wherein R3 and R4 are as defined in claim 1; or b) reducing a compound of the general formula III,
wherein R1, R2, R3 and R4 are as defined in claim 1; or c) reacting a compound having the general formula IV,
wherein R1 and R2 are as defined in claim 1, with a reactive derivative of a tertiary amine NR3R4R5, wherein R3, R4 and R5 independently are lower alkyl or R3 and R4 together form a saturated ring system; or
d) reducing a compound of the general formula V,
wherein R1, R2 , R3 and R4 are as defined in claim 1, and Q is oxygen or sulfur; or e) reductively alkylating a compound of the general formula VI,
wherein R1 and R2 are as defined in claim 1, with an aldehyde or
f) converting a compound of formula I as defined in
claim 1 to another compound of formula I;
and, if desired, separating a racemate obtained into optical isomers and/or forming an acid addition salt with an organic or inorganic acid.
EP93916373A 1992-07-22 1993-07-20 Pharmacologically active alpha-(tertiary-aminomethyl)-phenylmethanol derivatives Expired - Lifetime EP0651735B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE9202218A SE9202218D0 (en) 1992-07-22 1992-07-22 PHARMACOLOGICALLY ACTIVE ALFA (TERTIARY AMINOMETHYL) -BENZENEMETHANOL DERIVATIVES, PHARMACEUTICAL COMPOSITION CONTAINING THEM, THERAPEUTICAL USE THEREOF AND PROCESSES FOR THEIR PREPARATION
SE9202218 1992-07-22
PCT/SE1993/000635 WO1994002442A1 (en) 1992-07-22 1993-07-20 PHARMACOLOGICALLY ACTIVE α-[TERTIARY-AMINOMETHYL]-BENZENEMETHANOL DERIVATIVES

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EP0651735B1 EP0651735B1 (en) 1998-05-20

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DE19609847A1 (en) * 1996-03-13 1997-09-18 Gruenenthal Gmbh Dimethyl- (3-aryl-but-3-enyl) amine compounds as active pharmaceutical ingredients
WO1998046216A1 (en) * 1997-04-11 1998-10-22 Nippon Shinyaku Co., Ltd. Remedies for frequent urination and urinary incontinence
US6008412A (en) * 1997-10-14 1999-12-28 Eli Lilly And Company Process to make chiral compounds
US6323231B1 (en) 2000-02-17 2001-11-27 Abbott Laboratories Use of α1A adrenoceptor agonists with α1B and α1D antagonism for the treatment of stress urinary incontinence
US6503190B1 (en) 2000-09-29 2003-01-07 Ethicon Endo-Surgery, Inc. Vaginal pessary
TW200510298A (en) * 2003-06-13 2005-03-16 Theravance Inc Substituted pyrrolidine and related compounds

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US4349549A (en) * 1981-05-18 1982-09-14 Syntex (U.S.A.) Inc. Anti-hypertensive 1-substituted spiro(piperidine-oxobenzoxazine)s
PL140232B1 (en) * 1982-07-05 1987-04-30 Warszawskie Zaklady Farma Method of obtaining derivatives of 1-aryl-2-aminoestanole
EP0103830A3 (en) * 1982-09-22 1985-07-31 Bayer Ag Phenylethylemine derivatires as growth stimulators
EP0213108A3 (en) * 1985-06-26 1987-07-15 Kurt Dr. Burghart Pharmaceutical preparation containing an antihypotonic as the active agent
PH30083A (en) * 1991-02-25 1996-12-27 Lilly Co Eli Treatment of lower urinary tract disorders

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DE69318715D1 (en) 1998-06-25
TW261605B (en) 1995-11-01
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JPH07509699A (en) 1995-10-26
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HU9500175D0 (en) 1995-03-28
NO301760B1 (en) 1997-12-08
CA2140781C (en) 1998-09-29
CA2140781A1 (en) 1994-02-03
ZA935045B (en) 1994-02-07
CZ13395A3 (en) 1995-11-15
NO950177L (en) 1995-01-17
NZ254309A (en) 1996-08-27
KR950702522A (en) 1995-07-29
NO950177D0 (en) 1995-01-17
EP0651735B1 (en) 1998-05-20
US5527821A (en) 1996-06-18
SE9202218D0 (en) 1992-07-22
AU672989B2 (en) 1996-10-24
BR9306870A (en) 1998-12-08
RU2111205C1 (en) 1998-05-20
CN1085543A (en) 1994-04-20

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